Παρασκευή 12 Μαΐου 2017

Beta-catenin inhibitor BC2059 is efficacious as monotherapy or in combination with proteasome inhibitor bortezomib in multiple myeloma

Currently available treatment options are unlikely to be curative for the majority of multiple myeloma (MM) patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/beta-catenin signalling pathway, essential for self-renewal, growth and survival, has been found to be dysregulated in MM, particularly in advanced stages of disease. This provides the rationale for evaluating the novel beta-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo. Here we show nuclear localisation of beta-catenin in human myeloma cell lines (HMCL), consistent with activation of the canonical Wnt pathway. BC2059 attenuates   beta-catenin levels, in both the cytoplasm and the nucleus, reducing the transcriptional activity of the TCF4/LEF complex and the expression of its target gene axin2. Treatment of HMCL with BC2059 inhibits proliferation and induces apoptosis in a dose-dependent manner. This is also observed in HMCL-stromal cell co-cultures, mitigating the protective effect afforded by the stroma. Similarly, BC2059 induces apoptosis in primary MM samples in vitro, causing minimal apoptosis on healthy peripheral blood mononuclear cells (PBMC). Furthermore it synergizes with the proteasome inhibitor bortezomib both in HMCL and primary MM samples. Finally, in xenograft models of human myelomatosis, BC2059 delays tumour growth and prolongs survival with minor on-target side effects. Collectively these results demonstrate the efficacy of targeting the Wnt/ beta-catenin pathway with BC2059 both in vitro and in vivo, at clinically achievable doses. These findings support further clinical evaluation of BC2059 for the treatment of MM.



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